Regulation of gene expression at the level of translation is fundamentally important for the control of normal cell growth, development, differentiation, learning, memory, and the response to environmental stress, including viral infection. In particular, the translation of many eukaryotic capped, polyadenylated mRNAs is controlled at the initiation step, where the regulated assembly of a specialized, multiprotein complex is required to recruit the small ribosome subunit to the mRNA 5' terminus. The translation initiation factor components of this complex are capable of responding to different cellular signaling cascades, enabling a rapid response to diverse physiological effectors. Viral model systems have proven to be particularly useful in elaborating cellular translational control strategies because their successful replication absolutely requires viral mRNA translation. In their continued efforts to capture and engage the cellular protein synthesis machinery, viruses must effectively control the cellular signaling cascades that regulate translation. This investigation utilizes a herpesvirus family member, human cytomegalovirus (HCMV), as a probe to explore the complex circuitry regulating the initiation of mRNA translation. Although innocuous in most healthy individuals, HCMV is a widespread, opportunistic pathogen responsible for severe disease among the immunocompromised, including bone marrow and solid organ transplant recipients along with AIDS patients. In addition, congenital HCMV infection is the leading viral cause of birth defects in newborns. Our long-term overall objective is to understand how HCMV manipulates cellular translational control pathways to ensure that viral mRNAs can compete effectively with cellular mRNAs for access to translation initiation factors. As this process is critical for productive replication and reactivation from latency, our investigation is likely to reveal new targets for interfering with viral replication and new strategies for creating weakened, attenuated strains useful for vaccine development. In addition, these studies will provide insight into basic mechanisms of translational control that are likely to prove important in many human diseases, including cancer and diabetes, where the regulation of protein production is abnormal. We specifically propose to i) determine how HCMV infection affects eIF4F-core and associated components; ii) define the mechanism(s) by which PABP abundance is controlled translationally in HCMV-infected cells; and iii) evaluate the role of cellular eIF4E-kinases & eIF4E phosphorylation on viral replication & pathogenesis PUBLIC HEALTH RELEVANCE: Cellular protein production is critical for many important biological processes that impact upon human health including normal cell growth, development, learning, memory and proper response to environmental stress. While protein production is highly regulated and responsive to a variety of natural cues, the regulated process of protein production is disrupted in many human diseases, including cancer, diabetes, and viral infections, resulting in significant alterations in protein production. To understand how protein production is effectively regulated in cells, our studies exploit the power of human cytomegalovirus (HCMV) to capture, engage and manipulate the complex circuitry that is vital to properly control protein production. A comprehensive picture of how protein production is controlled could contribute to new strategies of treating many human diseases, including those caused by HCMV, which despite being innocuous in most healthy individuals, causes severe disease in individuals whose immune systems are not functioning properly (including transplant recipients along with AIDS patients) and is the leading viral cause of birth defects in newborns.